The genetic control and immunologic mechanisms of autoimmune disease is being investigated in the New Zealand strains of mice, their F1 hybrids, and recombinant-inbred lines derived from them. We have found 1) that enlargement of Lyt-2+ T cells is significantly associated with the titer of anti-erythrocyte autoantibody and degree of hemolytic anemia; 2) T cell suppression is defective in old NZB mice; 3) NZB, and particularly the (NZB x NZW) F1 hybrid, has a major resistance to induction of tolerance in the T cell subpopulation; 4) several abnormalities of proteins synthesized by lymphocytes from NZB mice can be demonstrated by two-dimensional gel electrophoresis. One, 16 kd in size, is observed only in enlarged NZB B cells, and may be associated with their pathologic spontaneous activation.